With increasing longevity, decreasing morbidity, and as older individuals expect to live intellectually challenging lives, cognitive aging has emerged as a major societal problem. Aging does not cause diffuse brain dysfunction but rather targets select brain areas, in particular the frontal lobes and the hippocampal formation. The hippocampal formation itself is made up of separate but interconnected subregions. A wide range of studies have established that hippocampal subregions are differentially vulnerable to mechanisms of dysfunction. Each subregion houses a molecularly-distinct population of neurons, providing a molecular basis for the observed differential vulnerability. A range of in vivo functional imaging and post-mortem studies suggest that: A) In contrast to early stages of Alzheimer's disease, normal aging differentially targets the dentate gyrus; B) the dentate gyrus is differentially vulnerable to elevations in blood glucose; and, C) the dentate gyrus differentially benefits from physical exercise. Additionally, preliminary data suggest that, D) age-related dentate gyrus dysfunction is linked to changes in the expression of molecules related to histone modification. In this proposal we link these observations into a general top-down model, suggesting etiologies, molecular mechanisms, and ways to ameliorate age-related hippocampal dysfunction. The general goal of this proposal is to test hypothesized elements of the model. The general approach is to use a high-resolution variant of functional magnetic resonance imaging that can assess the mouse hippocampal formation longitudinally over time. By mapping the effects various manipulations have on the living dentate gyrus, this approach will allow us to test specific hypotheses of the model. By confirming or modifying the top-down model, this proposal is potentially significant as it will expand our mechanistic understanding, but more importantly, it will directly lead to ways to ameliorate age-related hippocampal dysfunction. PUBLIC HEALTH RELEVANCE: With increasing longevity and decreasing morbidity, cognitive aging has emerged as a major societal problem. The short term goal of this proposal is to rely on previous findings to test hypotheses about etiologies and molecular mechanisms that contribute to cognitive aging. The general approach is to use a high-resolution variant of functional imaging that can assess the mouse brain longitudinally over time. More than just understanding mechanisms of dysfunction, the ultimate goal of this proposal is learn how to ameliorate cognitive aging.